21-acetoxy-11beta, 12beta-epoxy-5alpha-pregnan-3, 20-dione and process



United States Patent A non-exclusive, irrevocable, royalty-free licensein the invention herein described, throughout the world for all purposesof the United States Government, with the power to grant sublicenses forsuch purposes, is hereby granted to the Government of the United Statesof- Arnerica.

The present invention relates to steroid compounds, particularlyrelating to 21-acetoxy-115,12fi-epoxy-5apregnan-3,20-dione, to theintermediates fromed in its preparation from 115,125-epoxy-tigogeninacetate, and to the processes by which these compounds are obtained.

The compound 21-acetoxy-l1,8,12,53-epoxy-Set-pregnan- 3,20-dione is anintermediate in the production of useful corticoid hormones. Forexample, treatment with hydrobromic acid, followed by oxidation andpalladium reduction gives 2l-acetoxy-5a-pregnan-3,l1,20-trione.Bromination of the latter gives2,4-dibromo-21-acetoxy-5apregnan-3,l1,20-trione which on treatment withsodium iodide and chromous chloride reduction gives 21-acetoxy-4-pregnen-3,il,20-trione, more commonly known as dehydrocorticosterone,a useful cortical hormone. Alternatively, 2 l-acetoxy-l 1B,l2fi-epoxy-5a-pregnan-3 ,ZO-dione may be brominated, treated with sodiumiodide and reduced with chromous chloride to give ZI-acetOXy-IIB,l2fl-epoxy-4-pregnen-3,20-dione which on treatment with hydrogenfluoride gives Zl-acetoxy-llB-hydroxy-12afluoro-4-pregnen-3,20-dione, ahighly potent corticoid hormone.

An object of this invention is to provide a process for making thepregnaue derivative, 21-acetoxy-l15,12,8- epoxy-5a-pregnan-3,20-dione,useful as a precursor for making physiologically active compounds.Another object is to provide a process for proceeding from 11 8,125-epoxy-tigogenin acetate to the pregnane product retaining the epoxyfunction or a means of reforming it. A further object is to provide aprocess for utilizing hecogenin, a plant product. Other objects and afuller understanding of the invention may be had by referring to theaccompanying description, diagrams and claims.

The starting material, 11,8,125-epoxy-tigogenin acetate, was preparedfrom hecogenin. Hecogenin was acetylated and brominated, and theresulting l1a,23-dibromohecogenin acetate was reduced, as with sodiumborohydride in appropriate solvent, tolla,23-dibromo-12-hydroxy-hecogenin acetate. Dehydrobromination withstrong alkali in alcoholic solution formed the 1118,125- epoxy functionand debromination of this intermediate by heating in an aqueousalcoholic solution containing copper sulfate and metallic zinc gave115,12fl-epoxy tigogenin, which upon standing at room temperature inacetic anhydride-pyridine solution formed the 3-acetoxy derivative,115,125-epoxy-tigogenin acetate.

The preparation of 21-acetoxy-1IBJZfi-ePOXy-Sa-pregnan-3,20-dione from11,9,l2fi-epoxy-tigogenin acetate will now be described with referenceto the accompanying diagrams.

l 0.. O... lea K 1&

In accordance with the present invention 2l-acetoxy- 1l5,l2flepoxy-5a-pregnan-3,ZO-dione is prepared by the following series ofreactions: reacting 11,8,12B-epoxy tigogenin acetate (1) with diluteaqueous hydrochloric acid to produce the chlorohydrin,l2a-chloro-11fl-hydroxy-tigogenin acetate (II), heating II in aceticanhydride to open the F ring and formllfi-acetoxy-lZachloro-pseudotigogenin diacetate (III),dehydrochlorinating III in alcoholic, strong alkali solution to produce11,8,1Zfi-epoxy-pseudotigogenin (IV), acetylating IV in aceticanhydride-pyridine to give the diacetate (V), subjecting thepseudosapogenin diacetate (V) to oxidative cleavage, as obtained withchromium trioxide in cold, aqueous acetic acid, followed by alkalinehydrolysis such as potassium hydroxide in tertiary butanol to produce11,8,12fi-epoxy 3,8 hydrQXy-Sa-pregn-l6-en-20-one, and acetylating thelatter to obtain the 3,8-acetoxy derivative (VI), hydrogenating VI, asin the presence of the catalyst, 10% palladium on alumina, to produce3,8-acetoxy- 1l13,lZB-epOXy-Se-pregnan-ZO-one (VII), heating'VII inepoxide function, it was necessary to first change the aqueous alkalisolution such as potassium hydroxide in 115,12fi-epoxide function to thellfi-hydroXy-lZa-chlorofunctions.

It is interesting to note that heating IZa-ghlOI'O-llfihydroxy-tigogeninacetate (II) at 170 C. in acetic anhydride containing 1% acetic acidresulted in acylation of the llfl-hydroxy group as well as the 3pand26-hydroxy functions. Acylation of the llfi-hydroxy group under theseconditions is quite unexpected as ordinarily this hydroxy group is verydifiicult to acylate except in the presence of strong Lewis acids. Also,We were surprised to find that vigorous alkaline conditions such aspotassium or sodium hydroxide in alcohol solution, preferably methanolor ethanol for ease of solution, were required to convert thel1Bacetoxy-12u-chloro-moiety to the 115, 2B-epoxide. For example, if oneoxidizes compound III and then gives the product a mild saponification,11B- acetoxy-12a-chloro-3fi-hydroXy-Sa-pregn-16-en-20-one is obtainedrather than compound VI.

EXAMPLE 1 Preparation of '12a-chl0r0-1Jfi-hydroxy-tigogenin acetate (II)One gram of 11,8,12fl-epoxy-tigogenin acetate (I) was dissolved in ml.dioxane, to this was added 20 ml. 3 N HCl and 5 ml. water, and thesolution was stirred at room temperature for one hour. Seventy ml. waterwas added over 10 minutes with stirring, during which precipitationoccurred. After standing one hour the mixture was filtered, theprecipitate, IZa-ChlOIO-l 1,8- hydroxy-tigogenin acetate (II), washedwith water, and dried. Infrared analysis showed no epoxide (875 cmfband, but acetate (1735), hydroxyl (3480) and chloride (775 bands werepresent.

EXAMPLE 2 Preparation of 1Ifl-aceloxy-IZa-ch'loro-pseudozigogenindiacetate (III) Nine grams of the product of Example 1 was acetylated byheating at 170 C. for 2.5 hours in 23 ml. acetic anhydride containing asmall amount (1%) of acetic acid. The acetic anhydride was removed byvacuum evaporation to yield 10.4 grams of the triacetate, 115-acetoxy-l2achloro-pseudotigogenin diacetate (HI).

EXAMPLE 3 Preparation of 11,6,l2fi-epoxy-pseudotigogenin (IV) Theproduct of Example 2, 10.4 grams (III) was dissolved in 500 ml.methanol, 5 grams of potassium hydroxide was added with stirring, andthe solution allowed to stand 16 hours at room temperature. The solutionwas poured into two volumes of water and the product recovered by etherextraction. Yield: 7.4 grams of 11,9, 1Zfiepoxy-pseudotigogenin (IV).Infrared analysis showed strong band at 875 cm.- (epoxide), stronghydroxyl band, and absence of F ring.

EXAMPLE 4 Preparation of I15,125-epoxy-pseudotigogenin diacetate (V) The7.4 grams of 113,12,8-epoxy-pseudotigogenin from Example 3 was dissolvedin 20 ml. of pyridine, 15 ml. of acetic anhydride was added, and thesolution allowed to stand 16 hours at room temperature. The solution waspoured into four volumes of water, and the product, 9.2 grams ofl1B,12,8-epoxy-pseudotigogenin diacetate (V) recovered by etherextractions. Infrared characteristics were peaks at 1735 and 1250 cm.-(diacetate), 1685 cm.- (pseudosapogenin) and 875 cm. (oxide).

EXAMPLE 5 Preparation of 3B-acetaxy-1 1 3,1 ZB-epOxy-aIIOpregn -I 6-en-20-0ne (VI Two grams of the product of Example 4 (compound V) wasdissolved in 30 ml. acetic acid and cooled to about 15 C. Chromiumtrioxide (0.8 grams) dissolved in 15 ml. of 50% aqueous acetic acid wascooled to about C. and added dropwise, with stirring, to'the steroidsolution over a 10 minute time interval. The oxidation mixture wasallowed to warm to room temperature and stirring was continued for onehour. The mixture was poured into four volumes of water and the productrecovered by ether extraction. The ether was water washed, dried, andevaporated. The residue from the ether evaporation was dissolved in 50ml. t-butanol, one gram potassium hydroxide in 2 ml. water was added,and the mixture shaken at room temperature for three hours, The pregneneproduct, extracted with ether as before, was not recrystallized, butconverted to the acetate by standing in acetic anhydride-pyn'dinesolution overnight. The resinous product was purified by chromatographyto give 700 mg. of 3p-acetoxy-l1p,12B-epoxyallopregn-16-en-20-one (VI),M.P. 182-184 C., =!+103.5,

Am? 238.5 (log E=3.5)

EXAMPLE 6 Preparation of 3B-acetoxy-11fiJZB-epoxyallopregnan-ZO- one(VII) Three grams of compound VI (as prepared in Example 5) wasdissolved in 100 ml. ethyl ether and hydrogenated atmospheres hydrogenfor 2.5 hours.

EXAMPLE 7 Preparation of 3fi-hydroxy-11,3,1ZB-epOxy-Su-pregnan-ZO- one(VIII) 1.0 gram of compound VII was refluxed with a solution of 5 ml. ofacetone containing 0.5 gram of potassium hydroxide in 2.5 ml. of water,yielding 0.8 gram of compound VIII.

EXAMPLE 8 Preparation of21-acetoiy-3fi-hydroxy-I1,3,12fi-epoxy-5apregnan-Z 0-one (IX) A solutionof 0.5 gram of VIII in tetrahydrofuran and methanol was stirred withcalcium oxide and iodine until the solution decolorized. The crude iododerivative was refluxed with potassium acetate in acetone to give 0.2gram of IX.

EXAMPLE 9 Preparation of 21 -acet0xy-1 113,1 ZB-epOxy-SOL-pregnarz-3,20-diane (X) A solution of IX in acetone was cooled and treated withchromium trioxide in acetone in the presence of sulfuric acid. After ashort oxidation period the desired compound X was isolated.

We claim:

1. A process for the preparation of 2l-acetoxy-11fl,12,8-epoxy-5a-pregnan-3,20-dione comprising reacting115,12/3-epoxy-tigogenin acetate with dilute, aqueous hydrochloric acidto produce 12u-chloro-llB-hydroxy-tigogenin acetate, heating12a-chloro-1lfi-hydroxy-tigogenin acetate to about C. in aceticanhydride containing about 1% acetic acid to formllfi-acetoxy-lZa-chloropseudotigogenin diacetate, dehydrochlorinatingand deacetylating 1lfl-acetoxy-12e-chloro-pseudotigogenin diacetate inalcoholic, strong alkali solution to give 11 8, 128-epoxy-pseudotigogenin, acetylating 11/3,12,8-epoxypseudotigogenin byallowing it to stand in acetic anhydride-pyridine solution to form1118,12fi-epoxy-pseudotigogenin diacetate, oxidizing1lfi,l2fi-epoxy-pseudotigogenin diacetate with chromium trioxide incold, aqueous acetic acid followed by hydrolyzing the steroid oxidationproduct in tertiary butanol containing potassium hydroxide to give1l5,12/3-epoxy-3fl-hydroxy-5a-pregn-16- en-ZO-one, acetylating 1113,12Bepoxy-3fi-hydroxy-5apregn-16-en-20-one by allowing it to stand in aceticanhydride-pyridine solution to form 3-acetoxy-l1;8,12fl-epoxy-5a-pregn-16-en-20-one, hydrogenating3-acetoxy-l1,3,l2flepOxy-Sa-pregn-I6-en-20-one with hydrogen in thepresence of 10% palladium on alumina to give 3-acetoxy-11p,12,8-epoxy-5u-pregnan-20-one, heating 3-acetoxy-l1fi,12/3-epoxy-5-pregnan-20-one in aqueous alkali solution to obtain11p,12p-epoxy-3B-hydroxy-5e-pregnan-ZO-Qne, iodinating11,9,12fi-epoxy-3fl-hydroxy-5u-pregnan-ZObne with iodine and calciumoxide in tetrahydrofuran and methanol to give1113,l2fl-epoxy-3p-hydroxy-2l-iodo-5apregnan-ZO-one, heating this21-iodo derivative with potassium acetate in acetone to obtain2l-acetoxy-11B, l218-epoxy-3fl-hydroxy-5a-pregnan-20-one, oxidizing 21-acetoxy-llfiJZfi epoxy-3fl-hydroxy 5a pregnan-20-one with chromiumtrioxide in acetone in the presence of sulfuric acid and isolating theoxidation product, 21- acetoxy-l 1B, 1 2p?-epoxy-5a-pregnan-3,ZO-dione.

2. 11 B-acetoxy-l2a-chloro-pseudotigogenin diacetate.

3. 1113,1Zfi-epoxy-pseudotigogenin.

4. 11B,IZB-epoxy-pseudotigogenin diacetate.

5. 11B,l2B-epoxy-3fl-hydroxy-5a-pregn-16-en-20-one.

7 8 7. 11B,IZB-epbxy-BB-hydroxy-Zl-iodo 5a-pregnan-20- 2,819,264 Gouldet a1. Jan. 7, 1958 one. 7 7 2,874,154 Stork et a1 Feb. 17, 1959 T 12,944,052 Julian et a1 July 5, 1960 References Cited in the file of thispatent OTHER REFERENCES 6 UNITED STATES PATENTS JACS v01. 78, pp.2017-18 relifid on (1956), Fried 2,678,932 Buck et a1. May 18, 1954 eta1.

3. 11B,12B-EPOXY-PSEUDOTIGOGENIN. 5.11B,12B-EPOXY-3B-HYDROXY-5A-PREGN-16-EN-20-ONE.